<!DOCTYPE html PUBLIC "-//W3C//DTD HTML 4.01 Transitional//EN" "http://www.w3.org/TR/html4/loose.dtd">
<html>
<head>
<meta http-equiv="Content-Type" content="text/html; charset=UTF-8">
<title>Story</title>
</head>
<body>
	<p>The findings, published online this week in <em>Nature Communications</em>, could aid development of new drugs that exploit so-called flu protein 'pockets.'</p>
<p>Using powerful computer simulations on SDSC's new <em>Trestles</em>  system, launched earlier this year under a &#36;2.8 million National Science  Foundation (NSF) award, UCI's Rommie Amaro and Robin Bush together with  SDSC's Ross Walkercreated a method to predict how pocket structures on  the surface of influenza proteins promoting viral replication can be  identified as these proteins evolve, allowing for possible  pharmaceutical exploitation.</p>
<p>&quot;Our results can influence the development of new drugs taking  advantage of this unique feature,&quot; said Amaro, an assistant professor of  pharmaceutical sciences and computer science at UCI. Prior to joining  UCI in 2009, Amaro was a postdoctoral fellow in chemistry at UC San  Diego.</p>
<p>The search for effective flu drugs has always been hampered by the  influenza virus itself, which mutates from strain to strain, making it  difficult to target with a specific pharmaceutical approach. The most  common clinical flu treatments are broad-based and only partially  effective. They work by interrupting the action of an enzyme in the  virus called neuraminidase, which plays a critical role in viral  replication.</p>
<p>In 2006, scientists discovered that avian influenza neuraminidase  (N1) exhibited a distinctive, pocket-shaped feature in the area  pinpointed by clinically used drugs. They named it the 150-cavity.</p>
<p>Amaro and Bush, associate professor of ecology and evolutionary  biology, conducted research using resources at the San Diego  Supercomputer Center, as well as the National Institute for  Computational Sciences (NICS) to learn the conditions under which the  pockets form. They created molecular simulations of flu proteins to  predict how these dynamic structures move and change, as well as and  where and when the 150-cavity pockets will appear on the protein  surface.</p>
<p>This sequence analysis method could be utilized on evolving flu  strains, providing vital information for drug design, Amaro said.  &quot;Having additional antivirals in our treatment arsenal would be  advantageous and potentially critical if a highly virulent strain, for  example, H5N1, evolved to undergo rapid transmission among humans or if  the already highly transmissible H1N1 pandemic virus was to develop  resistance to existing antiviral drugs,&quot; she added.</p>
<p>Walker, an assistant research professor who runs the Walker Molecular  Dynamics Lab at SDSC, developed a customized version of the AMBER  software, a widely used package of molecular simulation codes, to run  these specific simulations on <em>Trestles</em> under the NSF's TeraGrid  Advanced User Support System. That included detailed performance tuning  including hard-coding atom counts, atom types and parameters, and being  able to use <em>Trestles</em> for uninterrupted two-week runs that together consumed more than one million SUs (single processor hours).</p>
<p>&quot;We initially used the <em>Athena</em> supercomputer at NICS, which  provided us with all the initial comparison data before Trestles came  online earlier this year,&quot; said Walker, who is also an adjunct assistant  professor in UC San Diego's Department of Chemistry and Biochemistry.  &quot;We had <em>Trestles </em>all ready to go as soon as the first H1N1 protein structure was available, and using the earlier work we did on <em>Athena</em>, we were able to put <em>Trestles</em> immediately to work to conduct simulations of the structure as part of this research.&quot;</p>
<p>Robert Swift and Lane Votapka of UCI, as well as Wilfred Li of UC San  Diego, also contributed to the study, which received support from the  National Institutes of Health and the NSF.</p>

<img src="http://images.sciencedaily.com/2011/07/110712122409.jpg" height="231" width="300" alt="" /><br />
<div id="caption" style="padding: 5px 0 10px 0"><em>The 150- and 430-loop structures are shown for 09N1 crystal structure (purple), 09N1 second most dominant molecular dynamics (MD) cluster representative structure (green backbone) and VN04N1 crystal structure (orange), indicating that the pandemic N1 adopts an open 150-loop conformation. Gly147, Ile149, Lys150 and Pro431 are shown in stick representation. This simulation was conducted on SDSC's Trestles supercomputer. (Credit: R. Amaro/UCI, Ross Walker, UCSD/SDSC)</em></div>
</body>
</html>